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Eur J Hum Genet. 2015 Nov;23(11):1482-7. doi: 10.1038/ejhg.2015.29. Epub 2015 Apr 29.

Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A.

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Greenwood Genetic Center, Greenwood, SC, USA.
Department of Translational Medicine and Neurogenetics, IGBMC, CNRS UMR 7104, INSERM U964, Strasbourg University, Strasbourg, France.
Department of Genetics and INSERM U1141, Robert Debré Hospital, Paris, France.
Laboratoire de diagnostic génétique, Faculty of Medicine and CHU Strasbourg, Strasbourg, France.
Department of Genetics, Robert Debré Hospital, Paris, France.
Fédération Hospitalo- Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon, Dijon, France.
Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est, Centre Hospitalier Universitaire Dijon, Dijon, France.
Equipe d'Accueil 4271, Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France.
Laboratoire de Génétique Moléculaire, Plateau Technique de Biologie, Centre Hospitalier Universitaire Dijon, Dijon, France.
Medical Genetics- Clinical Genetics Unit, CHU de Nantes, Nantes-Cedex, France.
Service de génétique médicale, CHU de Clermont-Ferrand, Clermont-Ferrand, France.
Department of Medical Genetics, Reference Center for Rare Diseases, Developmental Disorders and Multiple Congenital Anomalies, Arnaud de Villeneuve Hospital, Montpellier, France.
Department of Genetics and Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
Department of Neurosciences, Howard Hughes Medical Institute, Rady Children's Hospital, University of California, San Diego, La Jolla, CA, USA.
Departments of Pediatrics and Genetics, Division of Genetics and Metabolism, University of North Carolina, Chapel Hill, NC, USA.


The dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene, located on chromosome 21q22.13 within the Down syndrome critical region, has been implicated in syndromic intellectual disability associated with Down syndrome and autism. DYRK1A has a critical role in brain growth and development primarily by regulating cell proliferation, neurogenesis, neuronal plasticity and survival. Several patients have been reported with chromosome 21 aberrations such as partial monosomy, involving multiple genes including DYRK1A. In addition, seven other individuals have been described with chromosomal rearrangements, intragenic deletions or truncating mutations that disrupt specifically DYRK1A. Most of these patients have microcephaly and all have significant intellectual disability. In the present study, we report 10 unrelated individuals with DYRK1A-associated intellectual disability (ID) who display a recurrent pattern of clinical manifestations including primary or acquired microcephaly, ID ranging from mild to severe, speech delay or absence, seizures, autism, motor delay, deep-set eyes, poor feeding and poor weight gain. We identified unique truncating and non-synonymous mutations (three nonsense, four frameshift and two missense) in DYRK1A in nine patients and a large chromosomal deletion that encompassed DYRK1A in one patient. On the basis of increasing identification of mutations in DYRK1A, we suggest that this gene be considered potentially causative in patients presenting with ID, primary or acquired microcephaly, feeding problems and absent or delayed speech with or without seizures.

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